Variable and interactive effects of Sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regions.

Variable and interactive effects of Sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regions. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Variable and interactive effects of Sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regions. Joseph Giorgio, Caroline Jonson, Yilin Wang, Jennifer Yokoyama, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4804430/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Jul, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract The canonical AD pathological cascade posits that the accumulation of amyloid beta (Aβ) is the initiating event, accelerating the accumulation of tau in the entorhinal cortex (EC), which subsequently spreads into the neocortex. Here in a sample of over 1300 participants with multimodal imaging and genetic information we queried how genetic variation affects these stages of the AD cascade. We observed that females and APOE-ε4 homozygotes are more susceptible to the effects of Aβ on the primary accumulation of tau, with greater EC tau for a given level of Aβ. Furthermore, we observed for individuals who have rare risk variants in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) and/or APOE-ε4 homozygotes there was a greater spread of primary tau from the EC into the neocortex. These findings offer insights into the function of sex, APOE and microglia in AD progression, and have implications for determining personalised treatment with drugs targeting Aβ and tau. Health sciences/Neurology/Neurological disorders/Dementia/Alzheimer's disease Biological sciences/Neuroscience/Diseases of the nervous system/Alzheimer's disease Figures Figure 1 Figure 2 Figure 3 Full Text Additional Declarations Table 1 is available in the Supplementary Files section. There is NO Competing Interest. Supplementary Files giorgio2024tables.docx Table 1 giorgio2024supplementarymaterial.docx Supplementary Material giorgio2024supplementarymaterial.docx Cite Share Download PDF Status: Published Journal Publication published 01 Jul, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4804430","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":337336374,"identity":"4342d579-ff4a-4d86-a209-15f0d52dcbad","order_by":0,"name":"Joseph Giorgio","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+UlEQVRIiWNgGAWjYBACxgbGBiAlwcAvAeIwWIBFJYjSIjkDrEWCsBY4MLhBrBbm/sWNjyt+WcgZ324+9nFGhYScwQHmg7d58DlsxsNmw7N9EsZmd44lz9xwRsLY4ABbsjV+LQfbJBt7JBK33cgxZnzYJpG44QCPmTRRWjbPyP/M+PCfRP2GA/zf8Gvpb2yTbPgBNFwih5lxY4NEgsEBHjYCtjA2GzY2SBhL3DlmzDjjmIThzMNsxpZz8Ggx7D/+8GHDnzo5/tnNjxl7amzk+Y43P7zxBp+WGQlAq9qQRBQO41EOAvL8B4DkH2SRBgJaRsEoGAWjYMQBAMbKUrjlJGOiAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-3704-5977","institution":"University of California, Berkeley","correspondingAuthor":true,"prefix":"","firstName":"Joseph","middleName":"","lastName":"Giorgio","suffix":""},{"id":337336375,"identity":"90b96d02-e9cb-4358-ba40-c0bf0a12088b","order_by":1,"name":"Caroline Jonson","email":"","orcid":"","institution":"Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Caroline","middleName":"","lastName":"Jonson","suffix":""},{"id":337336376,"identity":"d0a0b293-3458-46d2-9086-ef9de00cb67f","order_by":2,"name":"Yilin Wang","email":"","orcid":"","institution":"Department of Statistics and Actuarial Science, The University of Iowa","correspondingAuthor":false,"prefix":"","firstName":"Yilin","middleName":"","lastName":"Wang","suffix":""},{"id":337336377,"identity":"74b28522-d36e-472b-bbba-7c04ce5ef8e3","order_by":3,"name":"Jennifer Yokoyama","email":"","orcid":"https://orcid.org/0000-0001-7274-2634","institution":"UCSF","correspondingAuthor":false,"prefix":"","firstName":"Jennifer","middleName":"","lastName":"Yokoyama","suffix":""},{"id":337336378,"identity":"0a2344a7-d507-4624-9636-c47502e5a594","order_by":4,"name":"Jingshen Wang","email":"","orcid":"","institution":"Division of Biostatistics, University of California Berkeley","correspondingAuthor":false,"prefix":"","firstName":"Jingshen","middleName":"","lastName":"Wang","suffix":""},{"id":337336379,"identity":"5f83c717-b3f8-4c7b-a9c0-d310a480b868","order_by":5,"name":"William Jagust","email":"","orcid":"https://orcid.org/0000-0002-4458-113X","institution":"University of California, Berkeley","correspondingAuthor":false,"prefix":"","firstName":"William","middleName":"","lastName":"Jagust","suffix":""}],"badges":[],"createdAt":"2024-07-26 00:00:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4804430/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4804430/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41467-025-60370-8","type":"published","date":"2025-07-01T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":62121044,"identity":"28f1e0b5-244e-4caa-80f5-f283f56f9ae9","added_by":"auto","created_at":"2024-08-09 13:56:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":510354,"visible":true,"origin":"","legend":"\u003cp\u003eCanonical AD cascade. The top panel shows the directed acyclic graph used to \u0026nbsp;model the potential pathways between genetic variables and pathology. Each arrow represents \u0026nbsp;a potential pathway from a genetic variant (grey node) through an upstream pathology (i.e. Aβ \u0026nbsp;or EC tau) that varies levels of downstream pathology (yellow node). The bottom panel \u0026nbsp;indicates the stages and spatial distribution of AD pathology throughout the cascade. We \u0026nbsp;modelled the initial seeding of tau using the EC region of interest. Early neocortical tau was \u0026nbsp;modelled using the meta temporal region of interest.\u003c/p\u003e","description":"","filename":"figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4804430/v1/60008ac38966e39b640dd526.png"},{"id":62121783,"identity":"3f13e406-5397-4050-a92d-df30110e9b6a","added_by":"auto","created_at":"2024-08-09 14:04:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":58773,"visible":true,"origin":"","legend":"\u003cp\u003eGenetic influences on Entorhinal Cortex (EC) tau. Lines show the estimated \u0026nbsp;marginal levels of tau pathology for individuals with varying genetic profiles at different levels \u0026nbsp;of Aβ. Bar graph shows estimated levels of tau pathology based on sex and TREM2 risk variant \u0026nbsp;carrier status. Different effects in the discovery sample for a. APOE-ε4, b. sex, c. interaction \u0026nbsp;of sex and TREM2 risk variant carrier status. Different effects in the replication sample for d. APOE-ε4 and e. sex. f. Causal path model to estimate EC tau. Values in parentheses indicate \u0026nbsp;presence of risk polymorphism or number of risk alleles. The path model shows the causal path \u0026nbsp;modelled whereby levels of EC tau are predicted by genetic variant, Aβ centiloid (CL) and \u0026nbsp;their interactions.\u003c/p\u003e","description":"","filename":"figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4804430/v1/95c7ad7aa0ac9967c8cc719f.png"},{"id":62121049,"identity":"659d8e4c-074f-487e-8ec8-1fcf6d75a44f","added_by":"auto","created_at":"2024-08-09 13:56:03","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":72173,"visible":true,"origin":"","legend":"\u003cp\u003eGenetic influences on MetaTemp tau. Lines show the estimated marginal levels of \u0026nbsp;MetaTemp tau pathology for individuals with varying genetic profiles at different levels of EC \u0026nbsp;tau. Different effects in the discovery sample for a. APOE-ε4, b. TREM2, and c. their \u0026nbsp;interaction. Different effects in the replication sample for d. APOE-ε4. e. causal path modelled \u0026nbsp;whereby levels of MetaTemp tau are predicted by genetic variant, Aβ centiloid, EC tau and \u0026nbsp;their interactions.\u003c/p\u003e","description":"","filename":"figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4804430/v1/7d716a4ed78807056bda1dcf.png"},{"id":85826636,"identity":"b24d5ac4-2845-4546-a85d-a042bd3eebb1","added_by":"auto","created_at":"2025-07-02 07:15:36","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1236012,"visible":true,"origin":"","legend":"Article File","description":"","filename":"giorgio2024main.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4804430/v1_covered_5575fe59-60e8-4171-9172-b713c122ca64.pdf"},{"id":62121043,"identity":"8bcbf8dd-c097-49a6-bcb5-7a7a31aeaa54","added_by":"auto","created_at":"2024-08-09 13:56:03","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":15555,"visible":true,"origin":"","legend":"Table 1","description":"","filename":"giorgio2024tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-4804430/v1/6f168a66258005c3dfeee194.docx"},{"id":62122524,"identity":"497790e4-281b-4bd0-a796-6df2059861ff","added_by":"auto","created_at":"2024-08-09 14:12:03","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":44647,"visible":true,"origin":"","legend":"Supplementary Material","description":"","filename":"giorgio2024supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-4804430/v1/0d507dafa0c60ebcf6d2c4fd.docx"},{"id":62121047,"identity":"e57ef17d-3872-4f93-8abf-ffb185be79fd","added_by":"auto","created_at":"2024-08-09 13:56:03","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":44647,"visible":true,"origin":"","legend":"","description":"","filename":"giorgio2024supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-4804430/v1/b643fa49895d5445cde69ce5.docx"}],"financialInterests":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e\n\u003cp\u003eThere is \u003cstrong\u003eNO\u003c/strong\u003e Competing Interest.\u003c/p\u003e","formattedTitle":"Variable and interactive effects of Sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regions.","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4804430/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4804430/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The canonical AD pathological cascade posits that the accumulation of amyloid beta (Aβ) is the initiating event, accelerating the accumulation of tau in the entorhinal cortex (EC), which subsequently spreads into the neocortex. Here in a sample of over 1300 participants with multimodal imaging and genetic information we queried how genetic variation affects these stages of the AD cascade. We observed that females and APOE-ε4 homozygotes are more susceptible to the effects of Aβ on the primary accumulation of tau, with greater EC tau for a given level of Aβ. Furthermore, we observed for individuals who have rare risk variants in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) and/or APOE-ε4 homozygotes there was a greater spread of primary tau from the EC into the neocortex. These findings offer insights into the function of sex, APOE and microglia in AD progression, and have implications for determining personalised treatment with drugs targeting Aβ and tau.","manuscriptTitle":"Variable and interactive effects of Sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regions.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-09 13:55:58","doi":"10.21203/rs.3.rs-4804430/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"af23294a-0058-4174-9374-c1b7ed76e6d8","owner":[],"postedDate":"August 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":35732694,"name":"Health sciences/Neurology/Neurological disorders/Dementia/Alzheimer's disease"},{"id":35732695,"name":"Biological sciences/Neuroscience/Diseases of the nervous system/Alzheimer's disease"}],"tags":[],"updatedAt":"2025-07-02T07:15:28+00:00","versionOfRecord":{"articleIdentity":"rs-4804430","link":"https://doi.org/10.1038/s41467-025-60370-8","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2025-07-01 04:00:00","publishedOnDateReadable":"July 1st, 2025"},"versionCreatedAt":"2024-08-09 13:55:58","video":"","vorDoi":"10.1038/s41467-025-60370-8","vorDoiUrl":"https://doi.org/10.1038/s41467-025-60370-8","workflowStages":[]},"version":"v1","identity":"rs-4804430","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4804430","identity":"rs-4804430","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}